Sweetening up antibodies

Certain individuals (neutralizers) infected with HIV are able to generate broadly neutralizing antibodies more efficiently than others (non-neutralizers). By comparing HIV-specific antibodies isolated from neutralizers and non-neutralizers, Lofano et al. found sialylation of the Fc domain to be higher in neutralizers. To understand the biological functions of Fc domain sialylation, the authors generated sialylated and nonsialylated isoforms of an HIV gp120-specific antibody, PGT121. By generating immune complexes of sialylated or nonsialylated PGT121 bound to fluorescently labeled HIV gp120, they found that sialylation enhanced the deposition of antigen in B cell follicles in a complement-dependent manner. Besides stressing the importance of the Fc domain in regulating antibody functions, the study also highlights the role of the complement pathway in driving humoral immunity.

Abstract

HIV-specific broadly neutralizing antibodies (bNAbs) confer protection after passive immunization, but the immunological mechanisms that drive their development are poorly understood. Structural features of bNAbs indicate that they originate from extensive germinal center (GC) selection, which relies on persistent GC activity. However, why a fraction of infected individuals are able to successfully drive more effective affinity maturation is unclear. Delivery of antigens in the form of antibody-immune complexes (ICs), which bind to complement receptors (CRs) or Fc receptors (FcRs) on follicular dendritic cells, represents an effective mechanism for antigen delivery to the GC. We sought to define whether IC-FcR or CR interactions differ among individuals who develop bNAb responses to HIV. Enhanced Fc effector functions and FcR/CR interactions, via altered Fc glycosylation profiles, were observed among individuals with neutralizing antibody responses to HIV compared with those without neutralizing antibody activity. Moreover, both polyclonal neutralizer ICs and monoclonal IC mimics of neutralizer antibodies induced higher antibody titers, higher-avidity antibodies, and expanded GC B cell reactions after immunization of mice via accelerated antigen deposition within B cell follicles in a complement-dependent manner. Thus, these data point to a direct role for altered Fc profile/complement interactions in shaping the maturation of the humoral immune response, providing insights into how GC activity may be enhanced to drive affinity maturation in next-generation vaccine approaches.

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